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Triglycerides in Cardiovascular Prevention - … · · 2016-04-16Triglycerides in Cardiovascular...
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Triglycerides in Cardiovascular Prevention
Nevrez Koylan M. D., FACC, FESC, EHSProfessor of Medicine
Anadolu Health Center
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Disclosures
Nothing to disclose related to this meeting and topic
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• An Overview of Triglycerides and Triglyceride Metabolism
• Triglycerides, Atherogenic Dyslipidemia andAtherosclerosis
• Triglycerides and Atherosclerotic Vascular Disease
• Treatment of Hypertriglyceridemia
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• An Overview of Triglycerides and TriglycerideMetabolism
• Triglycerides, Atherogenic Dyslipidemia and Atherosclerosis
• Triglycerides and Atherosclerotic Vascular Disease
• Treatment of Hypertriglyceridemia
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What is a Triglyceride?
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An Overview of Lipid Metabolism
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Cholesterol Esters in Lipoproteins
CHYLOMICRONS CHYLOMICRON REMNANTS
VLDLVLDL REMNANTS
LDL
HDL
Apo B48 Apo B48
Apo B100Apo A1
Apo B100
Watts GF, Ooi EMM, Chan DC. Nature Reviews Cardiology 2013, 10, 648–661
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Dietary Carbohydrate Transforms to VLDL
VLDL
Hudgins LC. Et al. J Lipid Res 2000, 41:595
DietaryCarbohydrate
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Development of Hypertriglyceridemia
VLDLChylo-
microns
DefectiveLipolysis byLipoproteinLipase
Remnants
Miller M. U Maryland Unpublished data
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• An Overview of Triglycerides and Triglyceride Metabolism
• Triglycerides, Atherogenic Dyslipidemia andAtherosclerosis
• Triglycerides and Atherosclerotic Vascular Disease
• Treatment of Hypertriglyceridemia
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Multiple Lipid Fractions Associated With CHD Risk
Adapted from Segrest JP, Garber DW, Brouillette CG, et al. Adv Protein Chem. 1994;45:303-369.
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Risk of CHD by Triglyceride LevelFramingham Heart Study
Castelli WP. Can J Cardiol 1988, 4:5A-10A
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Hypertriglyceridaemia, Triglyceride-rich Lipoproteins, And Atherogenesis
Inflammation
Coagulation
Endothelialdysfunction
Oxidativestress
Thrombosis
TRLTRL
remnant
Proinflammatory lipolysis products(e.g. Oxidized lipids, saturated FFA
LPLEndothelium
Subendothelialspace
TRLremnant
Foam cell formation
Macrophage
Monocyte
Foam cells
Watts GF, Ooi EMM, Chan DC. Nature Reviews Cardiology 2013, 10, 648–661
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Possible Atherogenic Changes Accompanying Hypertriglyceridemia
Hypertriglyceridemia
Increased VLDL Cholesterol rich
remnants
Increasedchylomicron
remnants
Coagulationchanges
Low HDL
Small dense LDL
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Atherogenic Dyslipidemia
Atherogenic dyslipidaemia: the combination of elevated TRL remnants and/or low HDL-C.• Triglycerides are predominantly carried in fasting conditions in very low-density lipoproteins (VLDLs) and their remnants, and postprandially in chylomicrons and their remnants.• The generic term ‘triglyceride-rich lipoprotein remnants’, therefore, relates to chylomicron and VLDL particles which have undergone dynamic remodelling in the plasma after secretion from the intestine(chylomicrons) or liver (VLDL)• Pattern of high TG, small, dense, LDL-C, and low HDL-C
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Pathogenesis of Atherogenic Dyslipidemia
VLDL
Chylo-microns
VLDLRemnants
DietaryFat
ChylomicronRemnants
DietaryCarbohydrates
LPL
SugarDiabetes,İnsulin
resistance
Hepatosteatosis
Apo B100
Apo B48
HDLLDL
Small denseLDL
Small denseHDL
Apo A1
CETP
CETP
CE CE
Plasmapool of
triglyceriderich
lipoproteins
Triglyceride Triglyceride
Watts GF, Ooi EMM, Chan DC. Nature Reviews Cardiology 2013, 10, 648–661
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Triglycerides and Lipoprotein Remnants
Nordestgaard BG, unpublshed results, 2010
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Remnant (Non- (HDL-C+LDL-C)) Cholesterol
McPherson R. “Non-(HDL-C + LDL-C)” as a Coronary Artery Disease Risk Factor. JACC 2013;61:437–9
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• An Overview of Triglycerides and Triglyceride Metabolism
• Triglycerides, Atherogenic Dyslipidemia and Atherosclerosis
• Triglycerides and Atherosclerotic Vascular Disease
• Treatment of Hypertriglyceridemia
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Triglycerides and CAD
• Difficult to show TG as an independent risk factor for CAD
• “Little old man in traffic”• Elevated TG is a risk when LDL/HDL ratio is > 5• In mixed dyslipidemia trials, apo B is a better risk
predictor than LDL• • Role of Non HDL
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Predictors of CHD Events in the ARIC Study
In 10-year follow-up of 12,339 men and women without CHD:
Multivariate predictors
LDL-C HDL-C Lp(a) TG (in women only)
Sharrett AR et al. Circulation 2001;104:1108–1113.
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Hazard Ratios for CHD or Ischemic Stroke Across Quantiles of Usual Triglyceride, HDL-C, and Non-HDL-C
Levels
Emerging Risk Factors Collaboration. JAMA 2009;302:1993–2000.
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Hypertriglyceridemia Increase CHD Risk in Patients with Low HDL Levels
Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.
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Increase in CVD Risk Due to Hypertriglyceridemia(Univariate analysis)
Hokanson JE, et al. J Cardiovasc Risk. 1996;3(2):213-219.
relative risks (RR) and 95%
confidence (CI) were calculated and
standardized with respect to a 1
mmol/L increase in triglyceride
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Available Prospective Studies Of Triglycerides And CHD In Essentially General Populations
Nadeem Sarwar et al. Circulation. 2007;115:450-458
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Triglycerides and MI Risk in 12510 Middle Aged Men
Stevanow L, Kjellstrom Tç Atherosclerosis 1999, 142:243-247
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Non-HDL Cholesterol and CVD Risk
• Non-HDL-C calculation• Non-HDL-C = TC – HDL-C
• Non-HDL-C goal
• 30 mg/dL above goal for LDL-C
• Significance of non-HDL-C• Encompasses all known and potential atherogenic lipid
particles
• (linearly proportional to Apo B)
• Has been shown to be a stronger predictor of cardiovascular death than LDL-C, especially in women
Bittner V. Curr Opin Lipidol. 2003;14:367-371.
Cui Y, et al. Arch Intern Med. 2001;161:1413-1419.
Ridker PM. JAMA. 2005; 294:326-333.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults. Circulation.2002;106:3143-3421.
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LDL-C and Non-HDL-C as Targets of Therapy
• LDL: major atherogenic lipoprotein
• VLDL: additional atherogenic lipoprotein
• Non-HDL: LDL + VLDL
• LDL cholesterol (LDL-C): traditional primary target for clinical intervention
• Non-HDL cholesterol (Non-HDL-C): appropriate target for clinical intervention
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Advantages of Non-HDL-C asTarget for Clinical Intervention
• Sum of all atherogenic lipoproteins (LDL + VLDL)
• Does not require fasting for accurate measurement
• Subsumes most cases of elevated triglycerides
• Growing evidence for greater predictive power than LDL-C
• Essentially equivalent to apolipoprotein B in predictive power
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Postprandial Triglyceride Levels in Subjects with and without Coronary Artery Disease (CAD)
Patsch JR et al. Arterioscler Thromb. 1992;12:1336-45.
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Remnant Cholesterol As A Causal Risk Factor For Ischemic Heart Disease
Varbo A et al. J Am Coll Cardiol. 2013;61:427–436.
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Remnant Cholesterol and CHD Risk
McPherson R. “Non-(HDL-C + LDL-C)” as a Coronary Artery Disease Risk Factor. JACC 2013;61:437–9
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• An Overview of Triglycerides and Triglyceride Metabolism
• Triglycerides, Atherogenic Dyslipidemia and Atherosclerosis
• Triglycerides and Atherosclerotic Vascular Disease
• Treatment of Hypertriglyceridemia
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Lowering LDL-C Decreases CHD Risk
34
LDL-C mg/dL (mmol/L)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - Plasebo
AFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Plasebo
CARE - Rx
LIPID - Placebo
CARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
40(1.0)
60(1.6)
80(2.1)
100(2.6)
120(3.1)
140(3.6)
160(4.1)
180(4.7)
Secondary prevention
Primary prevention
Rx - statin PRA – pravastatinATV - atorvastatin
200(5.2)
PROVE-IT - PRA
PROVE-IT – ATV
TNT – ATV10TNT – ATV80e
ven
t(%
)
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Residual Risk in Statin Trials
1o prevention 2o preventionHighrisk
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Risk Difference vs Placebo of High TG Subgroups Large-scale, Primary and Secondary CVD Prevention Trials
Trial (drug)
Primary endpoint: entire cohort (P)
Lipid subgroup criterion
Primary endpoint: subgroup post-hoc (P)
HHS (gemfibrozil) –34% (<0.02) TG >204 mg/dL LDL-C/HDL-C ratio >5.
–72% (0.005)
BIP (bezafibrate) –9% (0.26) TG ≥200 mg/dL –39.5% (0.02)
VA-HIT (gemfibrozil) –22% (0.006) TG ≥150 mg/dL –27% (0.01)
FIELD (fenofibrate) –11% (0.16) TG ≥204 mg/dL HDL-C <40 mg/dL
(men) or <50 mg/dL (women)
–27% (0.005)
ACCORD (fenofibrate) –8% (0.32) TG ≥204 mg/dL HDL-C ≤34 mg/dL
(Prespecified)
–31% (<0.05
JELIS (EPA) –19% (0.011) TG ≥150 mg/dL HDL-C <40 mg/dL
–53% (.043)
AIM-HIGH (niacin)
+2% (0.79) TG ≥200 mg/dL HDL-C <32 mg/dL
–36% (0.032)
ACCORD=Action to Control Cardiovascular Risk in Diabetes; AIM-HIGH=Atherothrombosis Intervention in MetS with Low HDL/High TG: Impact on
Global Health Outcomes; BIP=Bezafibrate Infarction Prevention; FIELD=Fenofibrate Intervention and Event Lowering in Diabetes; HHS=Helsinki Heart
Study; JELIS=Japan EPA Lipid Intervention Study; VA-HIT=Veterans Affairs HDL Intervention Trial.
Guyton JR et al. J Am Coll Cardiol. 2013;62:1580-4. Maki KC, Bays HE, Dicklin MR. J Clin Lipidol. 2012;6:413-26.
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Low Carb vs. Low Fat Diets on Triglycerides
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Statins Reduce CVD Events in HTG Patients
Trial (Subgroup, mg/dL)
(Drug)
Risk difference
vs placebo
P-value
Main Study Subgroup Main Study Subgroup
WOSCOPS (TG ≥148) (Pravastatin)
–31% –32% <0.001 0.003
CARE (TG ≥144) (Pravastatin)
–24% –15% 0.003 0.07
PPP Project (TG ≥200) (Pravastatin)
–23% –15% <0.001 0.029
4S (TG >159, HDL-C <39) (Simvastatin)
–34% –52% <0.001 <0.001
JUPITER (TG ≥150) (Rosuvastatin)
–44% –21% <0.001 NS
CTT (TG >177)
(Various)
–21% –24% <0.001 <0.001
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EPA+DHA & Lipid Levels in Patients w/ TG>500 mg/dLvs. Simvastatin
Harris WS et al. J Cardiovasc Risk 1997;4:385-91; Pownall HJ et al. Atherosclerosis 1999;143:285-97.
Davidson MH et al. Clin Ther. 2007;29:1354-67.
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n-3 Fatty Acid Randomized Controlled Trials Assessing Cardiovascular Outcomes
Trial, Year Population Interventions Compared Duration years Lipid Effects Endpoints RR (95% CI)
DART 1989 2,033 men with recent MI (mean 41 days)
2 servings/wk fatty fish (or fish oil capsules) vs other dietary advice
2 No change in TC IHD events Total deaths
0.84 (0.66-1.07)0.71 (0.54-0.93)
GISSI-P 11,324 men with recent
Usual care plus 882 mg/day 3.5 No change in TC, Major CV events 0.90 (0.82-0.99)
1999 MI (≤ 3 mo) EPA+DHA, vitamin E, both or neither
LDL-C or HDL-C; 5% decrease in
Non-fatal events Cardiac deaths
0.98 (0.83-1.15)0.78 (0.65-0.92)
TG Sudden deaths 0.74 (0.58-0.93)
JELIS 2007 18,645 patients with total cholesterol ≥ 6.5 mmol/l (with and without CHD history)
1.8 g/day EPA vs usual care 4.6 No change in TC, LDL-C or HDL-C; 6% decrease in TG
Coronary eventsNon-fatal eventsCoronary deathsSudden deaths
0.81 (0.69-0.95)0.81 (0.68-0.96)0.94 (0.57-1.56)1.06 (0.55-2.07)
GISSI-HF 6975 patients with heart
840 mg/day EPA+DHA vs 3.9 No change in TC, Total death 0.91 (0·83-0·99)
2008 failure placebo (not defined) LDL-C or HDL- Death orC; 5% decrease in hospitalization for 0.94 (0.89-099)TG CVD
Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald’s Heart
Disease: Expert Consult (2nd edition) Editor Christie M. Ballantyne (2014, in press)
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Recent n-3 Fatty Acid Randomized Controlled TrialsAssessing Cardiovascular Outcomes
RCT = randomized control trial; MI = myocardial infarction; IHD = ischemic heart disease; CV = cardiovascular; CHD = coronary heart disease; IGT
Iimpaired glucose tolerance; IFG = impaired fasting glucose; NR = not reported; TC = total cholesterol; HDL = high density lipoprotein; LDL = low
density lipoprotein; TG = triglycerides; SU.FOL.OM3 = Supplementation en Folates et Omega-3; ORIGIN = Outcome Reduction with Initial Glargine
Intervention.
Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald’s Heart Disease: Expert Consult (2nd edition) Editor Christie M.
Ballantyne (2014, in press)
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JELIS: Patient Subgroup - TG >150mg/dL and HDL <40mg/dL
Hazard ratio and P value adjusted for age, gender, smoking, diabetes, and
hypertension. HR = hazard ratio; CI = confidence interval. Saito Y, et al. Atherosclerosis. 2008;200(1):135-140.
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Fibrate Trials and CVD Events
Jun M, et al.; Lancet 2010; 375: 1875–84
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The Effect of Fibrates on CVD Events
Jun M, et al.; Lancet 2010; 375: 1875–84
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Effects of Fibrates on CHD Events by Cholesterol andTG Levels
Jun M, et al.; Lancet 2010; 375: 1875–84
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AIM-HIGHNiacin Plus Statin to Prevent Vascular Events
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AIM HIGH: Primary Outcome
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Fenofibrate Intervention andEvent Lowering in Diabetes (FIELD)
• 5-year study against a background of usual care, including the option to add other lipid-lowering therapies
9795 Type 2
Diabetes Patients
No clear indication for lipid
lowering therapy at baseline
FIELD Study Investigators. Cardiovasc Diabetol. 2004;3:9-24.
5 Years
or 500
CHD
Events
Fenofibrate 200 mg/day, n = 4895
Placebo, n = 4900
+Other lipid-lowering therapies
+Other lipid-lowering therapies
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FIELD: Primary and Secondary Endpoints
11% Reduction
P = 0.16
(Primary EP)
24% Reduction
P = 0.01
19% Increase
P = 0.22
11% Reduction
P = 0.035
21% Reduction
P = 0.003
(Secondary EP)
Keech A, et al. Lancet. 2005;366:1849-1861.
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FIELD: Total CVD Events in Patient Subgroups
ARR = 2.1%
NNT = 48
14% Reduction
P = 0.0214% Reduction
P = 0.06
ARR = 2.3%
NNT = 44
<40 mg/dL (men) and <50 mg/dL (women) at baseline Triglycerides ≥150 mg/dL and low HDL-C at baseline
Keech A, et al. Lancet. 2005;366:1849-1861.
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Action to Control Cardiovascular Risk inDiabetes (ACCORD) Study
• Question: Would statin plus a fibrate as compared with statin monotherapy reduce CVD in diabetics at high risk for CVD?
• 5518 patients with type 2 DM treated with open label simvastatin were treated with either masked fenofibrate or placebo
• Primary outcome measure: nonfatal MI, nonfatal stroke, or death from CV causes
• Follow-up: 4.7 years
• Results: Annual primary outcome was 2.2% in fenofibrate group and 2.4% in placebo group (NS)
• Annual rate of death was 1.5% in fenofibrategroup and 1.6% in placebo group (NS)
• Prespecified subgroup analysis suggested heterogeneity in treatment according to sex, with a benefit for men and possible harm for women (P = 0.01 for interaction)
• Possible benefit seen in fenofibrate group if baseline triglycerides high (>204 mg/dL) and HDL-C low (<34 mg/dL): primary outcome rate 12.4% in fenofibrate group vs. 17.3% inplacebo (P = 0.057 for interaction)
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
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Primary Outcome & Total Mortality
ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.
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ACCORD: Primary Outcome By Treatment Group and Baseline Subgroups
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ACCORD: Conclusion
• ACCORD Lipid does not support use of the combination of fenofibrate and simvastatin, compared to simvastatin alone, to reduce CVD events in the majority of patients with T2DM who are at high risk for CVD
• Subgroup analyses suggesting heterogeneity in response to combination therapy by gender or by the presence of significant dyslipidemia require further investigation
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Comparison Of ACCORD Subgroup Results With Those From Prior Fibrate Studies
Trial(Drug)
Primary Endpoint: Entire Cohort
(P-value)
Lipid Subgroup Criterion
Primary Endpoint: Subgroup
HHS (Gemfibrozil)-34% (0.02)
TG > 200 mg/dlLDL-C/HDL-C > 5.0 -71% (0.005)
BIP(Bezafibrate) -7.3% (0.24)
TG > 200 mg/dl-39.5% (0.02)
FIELD(Fenofibrate) -11% (0.16)
TG > 204 mg/dlHDL-C < 42 mg/dl -27% (0.005)
ACCORD(Fenofibrate) -8% (0.32)
TG > 204 mg/dlHDL-C < 34 mg/dl -31%
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Association Estimated By Meta-regression Between Extent Of TG-lowering And Reduction In Risk Of A Major CV Event In Large Controlled Trials Of
Fibrates
Nordestgaard BG et al. Lancet 2014;384:626–635.
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Approach for DM Patients with Dyslipidemia
• Start a Statin in any case!
• Combination therapy if necessary to achieve nonHDL targets
• DM with renal disease: statin plus ezetemibe(SHARP)/ba resin, statin plus fish oil, statin plus niacin (avoid feno)
• DM without renal disease but poorly controlled triglycerides or glucose: statin plus feno or fish oil/, niacin with caution
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New Drugs: DGAT Inhibitors
Harris WS, Bulchandani D. Curr Opin Lipidol 2006;17:387-393
Bays HE. Expert Rev. Cardiovasc. Ther. 6(3), 391–409 (2008)
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Apo C3 Inhibitors
• Apolipoprotein C-III (ApoC-III) is a small protein that resides on various lipoproteins
• Inhibits lipoprotein/hepatic lipases • Impairs hepatic uptake of triglyceride (TG)-rich lipoproteins (such as
lipoprotein remnants) • Generally promotes hypertriglyceridemia. • May contribute to insulin resistance • May contribute to atherosclerosis
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Hypertriglyceridemia and CVD- Conclusion
• Hypertriglyceridemia is an important but underestimated risk factor in the pathogenesis of atherosclerosis and must be treated
• Lifestyle modifications is the most important intervention• For TG ≥1000 mg/dL, consider fibrate, high-dose long chain Ω-3
fatty acids and niacin; for 500-999 mg/dL and no history of pancreatitis, consider statins or any of the above
• For TG 200-499 mg/dL, targets of therapy are non-HDL-C and LDL-C, generally using statins
• If LDL-C falls to <40 mg/dL, therapy may be continued in absence of intolerance